It is generally accepted that atherogenesis is triggered by primary injury to the endothelial lining of the arterial walls. This injury is believed to be the result of exposure of the underlying smooth muscle cells to several factors of noninfectious origin (hormones, low density lipoproteins, growth factors, among others). The prevailing view is that human atherosclerosis (AS) is a pleiotropic process with various causes. See Ross, R., The Pathogenesis of Atherosclerosis: An Update, New England J. Med.,314, 488 to 500 (1986).
A fundamentally new etiological factor: herpes virus infection was reported by Fabricant et al, who demonstrated that chickens infected with Marek Disease Virus (MDV) have an unusually high incidence of atherosclerotic plaque (ASP) in the arteries. See Fabricant, C. G. et al, Virus-Induced Cholesterol Crystals, Science, 181, 566 to 567 (1973); and Fabricant, C. G. et al, Virus-Induced Atherosclerosis, J. Exp. Med., 148, 335 to 340 (1978). Since that time data have been accumulated suggesting herpes virus in AS in humans. It was shown that different herpes viruses can alter smooth muscle cells lipid metabolism and induce cholesterol and cholesterol ester accumulation in these cells. See Fabricant, C. G. et al, Herpes Virus Infection Enhances Cholesterol and Cholesterol Ester Accumulation in Cultured Arterial Smooth Muscle Cells, Am. J. Pathol, 105, 176 to 184 (1981); Fabricant, C. G. et al, Herpes Virus-Induced Atherosclerosis in Chickens, Fed. Proc., 42, 2476 to 2479 (1983); Melnick, J. L. et al, Cytomegalovirus Antigen within Human Arterial Smooth Muscle Cells, Lancet, ii, 644 to 647 (1983); Gyorkey, F. et al, Herpesviridae in the Endothelial and Smooth Muscle Cells of Proximal Aorta in Atherosclerotic Patients, Exp. Mol. Pathol, 40, 328 to 339 (1984); Hajjar et al, Virus-Induced Atherosclerosis: Herpes Virus Infection Alters Aortic Cholesterol Metabolism and Accumulation, Am. J. Pathol., 122, 62 to 70 (1986); Adam et al, High Levels of Cytomegalovirus Antibody in Patients Requiring Vascular Surgery for Atherosclerosis, Lancet, 2, 291 to 293 (1987); Petrie, Association of Herpesvirus/Cytomegalovirus Infections with Human Atherosclerosis, Prog. Med. Virol., 35, 21 to 42 (1988); Grattan, M. T. et al, Cytomegalovirus Infection is Associated with Cardiac Allograft Rejection and Atherosclerosis, J. A. Med. Assoc. 261, 3561 to 3566 (1989); Mc Donald, K. et al, Association of Coronary Artery Disease in Cardiac Transplant Recipients with Cytomegalovirus Infection, Am. J. Cardiol., 64, 359 to 362 (1989); Visser et al, Granulocyte-Mediated Injury in Herpes Simplex Virus-Infected Human Endothelium, Lab. Invest., 60, 296 to 304 (1989); Melnick, J. L. et al, Possible Role of Cytomegalovirus in Atherogenesis, J. Am. Assoc., 263, 2204 to 2207 (1990); Bruggeman, C. A. et al, The Possible Role of Cytomegalovirus in Atherogenesis, Prog. Med. Virol., 38, 1 to 26 (1991); Melnick, J. L. et al, Accelerated Graft Atherosclerosis Following Cardiac Transplantation; Do Viruses Play a Role?, Clin Cardiol., 14 (Supp. II), 21 to 26 (1991); and Hajjar, D. P., Viral Pathogenesis of Atherosclerosis, Am. J. Pathol., 133, 1195 to 1211 (1991).
In addition the DNA of various herpesviruses showed positive hybridization with ASP DNA; see Benditt, E. P. et al, Viruses in the Etiology of Atherosclerosis, Proc. Natl. Acad. Sci., 80, 6386 to 6389 (1983); Pyrzak, R. et al, Detection of Specific DNA Segments of Marek's Disease Herpes Virus in Japanese Quail Susceptible to Atherosclerosis, Atherosclerosis, 68, 77 to 85 (1987); Petrie, B. L. et al, Nucleic Acid Sequences of Cytomegalovirus in Cultured Human Arterial Tissue, J. Inf. Dis., 155, 158 to 159 (1987); Yamashiroya, H. M. et al, Herpesviridae in Coronary Arteries and Aorta of Young Trauma Victims, Am. J. Pathol, 130, 71 to 79 (1988); and Hendrix, M. G. R. et al, The Presence of Cytomegalovirus Nucleic Acids in Arterial Walls of Patients Suffering From Grade III Atherosclerosis, Am. J. Pathol., 134, 1151 to 1157 (1989).
No systematic attempts to demonstrate a viral presence in ASP by direct isolation of infectious HSV from ASP and by detection of viral replication in ASP by Electron Microscopy have been reported. A viral presence in ASP would explain the presence of HSV-like DNA in ASP, and redirect research to determine the molecular mechanisms of viral involvement in etiology of atherosclerosis. In such a case, the possibility of a contamination of ASP in the blood vessels by HSV also has to be excluded.
None of the above references deals with the preparation of a vaccine against any form of the herpes virus. The following reference deals with the preparation of a herpes vaccine against Marek's Disease Herpes-Virus in chickens: Fabricant, J. et al, Vaccination Prevents Atherosclerosis Induced by Marek's disease Herpesvirus, College of Veterinary Medicine and Medicine, Cornell University, Ithaca and New York, N.Y. The reference appeared as an abstract in the Federation of American Societies for Experimental Biology, 65th Annual Meeting, Atlanta (1981).
The vaccine employed against Marek's Disease Herpesvirus in chickens was derived from Turkey herpesvirus (HVT). There is no indication that a vaccine against atherosclerosis caused by human herpes virus could be prepared. There is certainly no suggestion to employ a herpes vaccine containing homologous peptide sequences to those of the viral DNA found in strains of the herpes virus that effect humans.
U.S. Pat. No. 4,038,381 discloses a vaccine for the prevention and treatment of vascular conditions, comprising a combination of a tuberculosis antigen with an antiherpetic vaccine. There is no suggestion to employ the four polypeptides of the present invention as the active ingredients in the vaccine. The reference also states that the individual tuberculosis antigen and antiherpetic vaccine had no known per se ability in the prevention or treatment of vascular disease.